Unsaturated eicosanoic acids

ABSTRACT

Unsaturated eicosanoic acids and derivatives thereof which inhibit the synthesis of SRS-A are useful for treating and preventing asthma and allergic responses caused by SRS-A as well as useful in inhibiting inflammation.

BACKGROUND OF INVENTION

The material SRS-A (slow reacting substance of anaphylaxis) likehistamine is released from the cells of mammals during an allergicreaction. The SRS-A excreted by the cells contracts smooth muscle tissueproducing such allergic responses as asthmatic attacks. Thus, there hasbeen a great need for pharmaceuticals which inhibit the synthesis ofSRS-A to prevent its release by the cells during an allergic response.

Conventional anti-allergic drugs such as antihistamines, while effectivein neutralizing the histamine produced during an allergic response, havebeen ineffective in neutralizing or antagonizing the effects of SRS-A.This has limited the usefulness of these antihistamines asanti-asthmatic agents. Therefore, it has long been desired to developcompounds which will specifically inhibit the synthesis of SRS-A by thecells of a mammal to prevent its release during an allergic response andprevent the conditions associated with such an allergic response.

SUMMARY OF THE INVENTION

In accordance with this invention, we have discovered that compounds ofthe formula: ##STR1## wherein R is --COOR', or ##STR2## R₁ is hydrogenor fluoro; A and B are individually hydrogen or taken together form acarbon to carbon bond with a cis configuration; E and G are individuallyhydrogen or taken together form a carbon to carbon bond with a cisconfiguration with the proviso that at least one of A and B takentogether or E and G taken together form a carbon to carbon bond with acis configuration; and R', R₂ and R₃ are hydrogen or lower alkyl; and##STR3## where R is as above and Δ designates a double bond having a cisconfiguration, or pharmaceutically acceptable salts thereof inhibit thesynthesis of SRS-A and are useful for treating asthma or allergicresponses caused by SRS-A. The compounds of formulae I and II alsoinhibit inflammation.

DETAILED DESCRIPTION

The term "halogen" as used herein includes all forms of halogens, i.e.chlorine, fluorine, bromine and iodine with chlorine and bromine beingpreferred. The term "lower alkyl" designates any saturated straight orbranched aliphatic hydrocarbon group containing from 1 to 7 carbon atomssuch as methyl, ethyl, isopropyl, or propyl, butyl, t-butyl, etc. Theterm "lower alkoxy" includes any lower alkoxy group containing from 1 to7 carbon atoms, such as methoxy, isopropoxy, ethoxy, etc.

The term "lower alkanoyloxy" designates residues of saturated aliphaticacids containing from 2 to 7 carbon atoms. Among these lower alkanoyloxygroups are included acetoxy, pivalyloxy, etc. As used herein, the term"aryl" signifies mononuclear aromatic hydrocarbon groups such as phenylwhich can be unsubstituted or substituted in one or more positions witha lower alkyl and polynuclear aryl group such as naphthyl anthyryl whichcan be unsubstituted or substituted with one or more of the lower alkylgroups. The preferred aryl groups are phenyl or tolyl. The conventionalhydrolyzable ether group utilized to protect an --OH group can be anyconventional ether which hydrolyzes to a hydroxy group upon etherhydrolysis. Among the preferred ether protecting groups are includedtetrahydropyranyl, t-butyl and aryl methyl ethers. Among the preferredaryl methyl ethers are benzyl.

The compounds of formulae I and II where R is --COOH can be used inaccordance with this invention in their salt form. Any conventionalpharmaceutically acceptable basic salts of the compound of formulae Iand II can be utilized. Among the conventional basic salts which can beutilized are included metal ions e.g. aluminium, alkali metal salts suchas sodium or potassium, alkaline earth metal salts such as calcium ormagnesium, and ammonium or substituted ammonium salts for example thosefrom lower alkylamines, such as triethylamine, hydroxy-lower alkylaminessuch as 2-hydroxyethylamine, tris(hydroxymethyl)aminomethane,bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine, or from procaine,dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine,N-ethylpiperidine, N-benzyl-α-phenethylamine, dehydroabietylamine,N,N'-bis-dehydrobietylethylenediamine, or bases of the pyridine typesuch as pyridine, collidine or quinoline. These salts can be formed fromthe compounds of formulae I and II where R is --COOH by treating thisacid in a conventional manner with a base such as an metal hydroxide,ammonium hydroxide or an amine base.

The compounds of formulae I or II, as well as their pharmaceuticallyacceptable salts, are inhibitors of SRS-A synthesis and are useful as intreating or preventing and other allergic responses caused by SRS-A,expecially broncoconstriction. The compounds of this invention are alsouseful as antiinflammatory agents.

The compounds of formulae I or II, as well as salts thereof orcompositions containing effective amounts of these amounts of thesecompounds are useful for treating or preventing asthma or other allergicresponses to SRS-A or as antiinflammatory agents. These compounds can beadministered by methods well known in the art. They can be administered,either singly or with other pharmaceutical agents, e.g., antagonists ormediators of anaphylaxis such as antihistamines, or anti-asthmaticsteroids such as prednisone and prednisolone, orally, parenterally or byinhalation, e.g., in the form of an aerosol, micropulverized powder ornebulized solution. For oral administration they can be administered inthe form of pills, tablets, capsules, e.g., in admixture with talc,starch, milk sugar or other inert ingredients, i.e. pharmaceuticallyacceptable carriers, or in the form of aqueous solutions, suspensions,encapsulated suspensions, gels, elixirs or aqueous alcoholic solutions,e.g., in admixture with sugar or other sweetening agents, flavorings,colorants, thickeners and other conventional pharmaceutical excipients.For parenteral administration, they can be administered in solutions orsuspension, e.g., as an aqueous or peanut oil solution or suspensionusing excipients and carriers conventional for this mode ofadministration. For administration as aerosols, they can be dissolved ina suitable pharmaceutically acceptable solvent, e.g., ethyl alcohol orwater or combinations of miscible solvents, and mixed with apharmaceutically acceptable propellant. Such aerosol compositions arepackaged for use in a pressurized container fitted with an aerosol valvesuitable for release of the pressurized composition. Preferably, theaerosol valve is a metered valve, i.e., one, which on activation,releases a predetermined effective dose of the aerosol composition.

In practicing the method of the invention, the dose of compounds offormulae I or II or their salts to be administered and the frequency ofadministration will be dependent on the potency and duration of activityof the particular compound to be administered and on the route ofadministration, as well as the severity of the condition, age of themammal to be treated, etc. Doses of compounds of formulae I or II orsalts thereof contemplated for use in practicing the method of theinvention are about 0.001 to about 50 mg per kilogram of body weight perday, preferably about 0.01 to about 5 mg per kilogram of body weight perday, either as a single dose or in divided doses administered orally.

The compound of formula I where R₁ is hydrogen and R is other than anester group is prepared by reacting a compound of the formula:

    HC.tbd.C--CH.sub.2 --CH.sub.2 --CH.sub.2 --R"              IV

wherein R" is --COOH or ##STR4## and R₂ and R₃ are as above, with acompound of the formula: ##STR5## wherein X is halogen, A, B, and E andG are above with the proviso that at least one of A and B taken togetheror E and G taken together form a carbon to carbon bond with a cisconfiguration.

This reaction is carried out by first converting the compound of formulaIV to the corresponding magnesium halide which has the formula:

    XMg C.tbd.C--CH.sub.2 --CH.sub.2 --CH.sub.2 --R'"          VII

wherein X is as above; and R'" is --COOMgX, or COOY or ##STR6## and Y isan alkali metal cation.

This reaction is carried out by treating the compound of formula IV witha lower alkyl magnesium halide such as ethyl magnesium halide.Generally, this reaction is carried out in the presence of an inertorganic solvent. Any conventional inert organic solvent can be utilized.Among the preferred solvents are the ether solvents such astetrahydrofuran, dioxane, diethyl ether, etc. In carrying out thisreaction, temperatures and pressures are not critical, and this reactioncan be carried out at room temperature and atmospheric pressure.Generally, temperatures of from -50° C. to +100° C. are preferred withtemperatures of from -10° C. to +50° C. being especially preferred.Furthermore, this reaction is carried out under an inert atmosphere. Anyconventional inert gas can be utilized to create the inert atmosphere.Generally, this reaction is carried out in the presence of argon,nitrogen, helium or krypton.

In preparing the compound of formula VII where R'" is COOY, the compoundof formula IV is first treated with an alkali or alkaline earth metalbase such as lithium or sodium hydroxide to form the acid salt prior totreatment with a lower alkyl magnesium halide to form the magnesiumhalide of formula VII. Any conventional method of converting an organicacid to its alkali metal or alkaline earth metal salt form can be usedin this reaction.

The compounds of formula I where R₁ is hydrogen is formed by reactingthe compound of formula V with the compound of formula VII. Generally,this reaction is carried out in the presence of a copper orcopper-containing catalyst. Any conventional copper-containing catalystsuch as a copper salt can be utilized in carrying out this reaction. Thepreferred copper salt is Copper I cyanide. Generally, this reaction iscarried out in an inert atmosphere utilizing the same conditions asdescribed in connection with the formation of the compound of formulaVII from the compound of formula IV. In fact, it is preferred to carryout this reaction in the same reaction medium that was utilized forforming the compound of formula VII from the compound formula IV withoutisolating the compound of formula VII from the reaction medium.

The compound of formula I where R₁ is fluorine is formed by firstreacting a compound: ##STR7## where R₂ and R₃ are as above with acompound of the formula V. This reaction is carried out in the samemanner as described in connection with the conversion of the compoundIV, by reaction with the compound of formula V, to the compound offormula I where R₁ is hydrogen. In the conversion of the compound ofIV-A to the compound of formula I where R₁ is fluorine, the compound offormula IV-A is first converted, as described in connection with thecompound formula IV to the compound of formula VII to a compound of theformula: ##STR8## where X, R₂ and R₃ are as above by reaction with alower alkyl magnesium halide.

The compound of formula VII-A by reaction with the compound of formula Vis converted to a compound of the formula: ##STR9## wherein A and B andE and G are as above, with that at least one of A and B or E and G takentogether form a carbon to carbon bond with a cis configuration; and R₂and R₃ are as above.

The compound of formula I-B or the compound of formula I where R isother than --COOR can be converted to the corresponding free acid:##STR10## at least one of A and B or E and G taken together form acarbon to carbon bond with a cis configuration, by hydrolysis with adilute aqueous mineral acid such as hydrochloric acid, sulfuric acid,etc. Any conventional method of hydrolysis with a dilute aqueous mineralacid can be utilized to effect this conversion. The compound of formulaI-C or the compound of formula I where R is COOH can be esterified byany conventional means of esterification such as reaction with a loweralkyl halide to produce the ester of ##STR11## wherein R₁, A and B and Eand G are as above, with the proviso that at least one of A and B or Eand G taken together form a carbon to carbon bond with a cisconfiguration and R₅ is lower alkyl.

In carrying out these hydrolysis and esterification reactions, it isgenerally preferred to carry out these reactions in the presence of aninert gaseous atmosphere.

In accordance with this invention, the compound of formula V where A andB and E and G form carbon to carbon bonds having a cis configuration,i.e. a compound of the formula: ##STR12## wherein X is as above and Δdesignates a cis configuration about the double bond is produced from acompound of the formula:

    HO--CH.sub.2 --C.tbd.C--CH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.3                                     IX

via the following intermediates ##STR13## wherein X is as above; and R₉is hydrogen or taken together with its attached oxygen atom forms anether protecting group, preferably tetrahydropyranyl, and Δ is as above.

The compound of formula IX is converted to the compound of formula X byhydrogenation in the presence of a selective hydrogenation catalyst. Anycatalyst which selectively reduces only the triple bond (acetylenelinkage) to a double bond can be utilized in carrying out thisconversion. Among the preferred selective hydrogenation catalysts arethe palladium catalysts which contain a deactivating material such aslead, lead oxide or sulfur. Among the preferred selective hydrogenationcatalysts are included the palladium-lead catalysts of the typedisclosed in Helv. Chim. Acta. 35 pg. 446 (1952) and U.S. Pat. No.2,681,938 to Lindlar. These catalysts are commonly known as Lindlarcatalysts. The hydrogenation of the compound of the formula IX using aselective hydrogenation catalyst produces a double bond containing a cisconfiguration. Therefore, selective hydrogenation of the compound offormula IX containing two acetylenic linkages produces two double bondshaving a cis configuration.

The compound of formula X is converted to the compound of formula XI bytreating the compound of formula X with a halogenating agent. Anyconventional halogenating agent can be utilized in effecting thisconversion. Among the preferred halogenating agents arecarbontetrachloride and triphenylphosphine. Any of the conditionsconventional in halogenating a hydroxy group with conventionalhalogenating agents can be utilized in carrying out this reaction.

The compound of formula XI can be converted to the compound of formulaXII by treating the compound of formula XI with a compound of theformula

    HC.tbd.C--CH.sub.2 --OR.sub.9                              XIII

wherein R₉ is hydrogen or an ether protecting group.

In carrying out this reaction, the compound of formula XIII is convertedto its corresponding magnesium halide of the formula:

    XMgC.tbd.C--CH.sub.2 R.sub.13                              XIII-A

wherein R₁₃ is --OR₉ or --OMgX; X is as above; and R₉ ' is an etherprotecting group, by reacting the compound of formula XIII with a loweralkyl magnesium halide. Any conventional method of forming a magnesiumhalide salt such as described hereinbefore in connection with theformation of a compound of formula VII can be utilized in thisconversion. On the other hand, the compound of formula XIII can beconverted to a compound of the formula:

    YC.tbd.C--CH.sub.2 --R.sub.13 '                            XIII-B

where R₁₃ ' is --OR₉ or --OY; Y is an alkali metal cation preferablylithium; and R₉ ' is as above, by reaction with an alkali metal alkylsuch as n-butyl lithium. In carrying out this reaction any conventionalmethod of forming an alkali metal acetalide can be used to convert thecompound of formula XIII to a compound of formula XIII-B. The compoundof formula XII is produced by reacting the compound of formula XIII-A orXIII-B with the compound of formula XI. Wherein R₉ in the compound offormula XIII is hydrogen, the compound of formula XIII-A is formed whereR₁₃ is --OMgX and the compound of formula XIII-B is formed where R₁₃ is--OY. In forming the compound of formulae XIII-A and XIII-B, an inertatmosphere, as described hereinbefore, is generally used.

The compound of formula XI is converted to the compound of formula XIIby reaction with the compound of formulae XIII-A or XIII-B. Thisreaction is carried out by utilizing the same procedure as describedhereinbefore in connection with reacting the compound of formula V withthe compound of formula VII to produce a compound of formula I. Ingeneral, this reaction is carried out under an inert atmosphere. Thecompound of formula XII where OR₉ forms an ether protecting group isconverted to the compound of formula XII where R₉ is hydrogen byconventional ether cleavage such as hydrolysis. Generally, it ispreferred to carry out this hydrolysis by treatment with a strongorganic acid such as p-toluene sulfonic acid.

The compound XII where R₉ is hydrogen is converted to the compound offormula V-A by treating the compound of formula XII where R₉ is hydrogenwith a halogenating agent such as phosphorous tribromide in pyridineutilizing conditions conventionally used with respect to thesehalogenating agents.

Compounds of formula V where A and B are hydrogen and E and G form acarbon to carbon bond having a cis configuration, i.e. compounds of theformula: ##STR14## wherein Δ and X are as above, are prepared from thereaction product of ##STR15## wherein R₈ is aryl and X is as above, viathe following intermediates: ##STR16## wherein Δ and R₉ are as above.

The compoud of formula VI is condensed with the compound of formula XIVto produce the compound of the formula XV by means of a Wittig reaction.Any of the conditions conventionally used in Wittig reactions can beused in carrying out this reaction. Generally this reaction is carriedout in the presence of an ether solvent and a base. Among the preferredbases are the silyl bases such as sodium bistrimethylsilylamide. TheWittig reaction produces the double bond in the compound of formula XVwith a predominantly cis configuration.

The compound of formula XV is converted to the compound of formula XVIby treating the compound of formula XV with a halogenating agent such asdescribed hereinbefore. The preferred halogenating agent for use in thisreaction is phosphorous tribromide in the presence of an organic basicsolvent such as pyridine. Any of the conditions conventionally used withthese halogenating agents can be utilized in carrying out this reaction.

The compound of formula XVI is converted to the compound XVII byreacting the compound of formula XVI with the compound of formulaXIII-B. This reaction is carried out in the presence of an organicsolvent at a temperature of from -70° C. to 25° C. with temperatures offrom -30° C. to +25° C. being preferred. The preferred solvents in thisreaction are tetrahydrofuran, hexamethyl phosphoric acid triamidemixtures of these, as well as diethylether dioxane, etc.

Where R₉ in the compound of formula XIII is --OY, the compound offormula XVII is produced where R₉ is hydrogen. On the other hand, if R₉in the compound of formula XIII-B is an ether-protecting group, thecompound of formula XVII is formed where R₉ is an ether-protectinggroup. This ether-protecting group can be converted to the free hydroxycompound of formula XVII, i.e. the compound of formula XVII where R₉ ishydrogen, by acid hydrolysis. Any conventional method of hydrolyzing anether group to the corresponding hydroxy compound can be utilized. Amongthe preferred method is by the use of a strong organic acid such asp-toluene sulfonic acid in an inert organic solvent such as methylalcohol.

The compounds of formula XVII where R₉ is hydrogen is converted to thecompound of formula V-B by halogenation. Any conventional method ofhalogenation such as by use of conventional halogenating agents such asphosphorus tribromide can be utilized to carry out this reaction.

The compound of formula V wherein A and B form a cis double bond and Eand G are hydrogen, i.e. a compound of the formula ##STR17## where Δ andX are as above, can be prepared from a compound of the formula

    HOCH.sub.2 --C.tbd.C--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.3                          XVIII

via the following intermediates ##STR18## wherein Δ, X and R₉ are asabove.

The known compound of formula XVIII is converted to the compound offormula XIX by selective hydrogenation in the same way as hereinbeforedescribed in connection with the conversion of the compound of theformula IX to a compound of the formula X. The double bond produced byselective hydrogenation in the compound of formula XIX has a cisconfiguration. The compound of formula XIX is converted to the compoundof formula XX by halogenation such as described hereinbefore inconnection with the halogenation of formula X to the compound of formulaXI. The compound of formula XX is converted to the compound of formulaXXI by reaction with the compound of formula XIII-A or XIII-B in thesame manner as described in connection with the conversion of thecompound of formula XI to the compound of formula XII. The compound offormula XXI where R₉ is hydrogen is converted to the compound of formulaV-C by halogenation in the same manner as disclosed in connection withthe conversion of the compound of formula XVII to the compound offormula V-B. Where R₉ is an ether-protecting group in the compound offormula XXI this ether protecting group is hydrolyzed by acid hydrolysisto form the corresponding hydroxy group before it is halogenated in theaforementioned manner to produce the compound of formula V-C. Hydrolysisis carried out in the same manner as described in connection with thecompound of formula XVII where R₉ is an ether protecting group.

The compound of formula IV where R" is --COOH, is a known compound. Thecompound of formula IV where R is ##STR19## can be prepared by reactingthe compound of IV where R" is --COOH with a compound of the formula:##STR20## where R₂ and R₃ are as above.

This reaction is carried out by reacting the compound of formula IVwhere R" is --COOH with the compound of formula XXIII in an organichydrocarbon solvent while removing water from the reaction medium. Ingeneral, this reaction is carried out at reflux while removing the waterformed during this reaction. Any conventional method of removing watersuch as by azeotropic distillation can be utilized in this reaction. Incarrying out this reaction, any conventional inert hydrocarbon solventsuch as xylene, toluene, benzene, etc. can be utilized. In like manner,the compound of formula IV-A can be produced from a compound of formula:##STR21## by reacting the compound of formula IV-D with the compound offormula XXIII. This reaction is carried out in the same manner asdescribed in connection with the reaction of the compound of formula IVwhere R" is COOH with the compound of formula XXIII.

The compound of formula IV-D is prepared from a compound of formula

    CH.tbd.C--CH.sub.2 --CH.sub.2 --CH.sub.2 OH                XXV

via the following intermediates: ##STR22## where --OR₁₇ is a leavinggroup.

The compound of formula XXV is converted to the compound of formula XXVIby oxidation. Any conventional oxidizing agent used for convertingalcohols to aldehydes can be used in this reaction. The preferredoxidizing agent for use in this reaction is pyridinium chlorochromate.The compound of formula XXVI can be converted to the compound of formulaXXVII by conventional procedures for a cyanohydration reaction such asby treating the compound of formula XXVI with an alkali metal cyanidesuch as potassium or sodium cyanide. Generally this reaction is carriedout at room temperature and atmospheric pressure. If desired, higher orlower temperatures can be utilized. Furthermore, this reaction isgenerally carried out in an aqueous medium.

The compound of formula XXVII is converted to the compound of formulaXXVII by converting the hydrogen on the hydroxy group in the compound offormula XXVII to a leaving group. Any conventional leaving group can beutilized. Among the preferred leaving groups are tosyloxy and mesyloxywith mesyloxy being especially preferred. Any conventional method ofconverting the hydroxy group to a mesyloxy or tosyloxy substituent canbe utilized in converting the compound of formula XXVII to the compoundof formula XXVIII. The compound of formula XXVIII is converted to thecompound of formula XXIX by treating the compound of formula XXVIII withan alkali metal fluoride. In carrying out this reaction, temperatures offrom 50° C. to 150° C. are utilized. Generally, this reaction is carriedout in a high boiling organic solvent, i.e. an organic solvent boilingat 50° C. or greater. Among the preferred solvents that can be utilizedare diethylene glycol, pentane, benzene, toluene, and dimethylacetamide. The compound of formula XXIX is converted to the compound offormula IV-D by hydrolysis. Any conventional method of basic hydrolysissuch as by treatment with an aqueous base such as potassium or sodiumhydroxide can be utilized in carrying out this reaction.

The compound of formula IV-D can also be prepared by alkylating acompound of the formula: ##STR23## with a substituted alkyl halide ofthe formula:

    (R.sub.15).sub.3 --Si--C.tbd.C--CH.sub.2 --CH.sub.2 --X    XXXI

wherein R₁₅ and R₁₉ are lower alkyl; X is as above, to produce acompound of the formula: ##STR24##

This alkylation reaction is carried out by first treating the compoundof formula XXX with an alkali metal base such as sodium hydride in aninert organic solvent to form the salt of the compound of formula XXXand then adding the compound of formula XXXI to the reaction mixturecontaining this salt. In carrying out this reaction, any conventionalbase can be utilized. Among the preferred bases are the alkali metalhydrides and the alkali metal lower alkoxides. In carrying out thealkylation reaction, both steps can be performed in the presence of aninert organic solvent. Any conventional inert organic solvent can beutilized. Among the preferred solvents are the ether solvents such astetrahydrofuran, diethyl ether, as well as other solvents such asacetamide, dioxane, etc. While both the addition of the base and thesubsequent reaction with the compound of formula XXXI can be carried outat room temperatures, it is generally preferred to carry out thesubsequent reaction at higher temperatures, i.e. 40° to 100° C.Therefore, in accordance with the preferred embodiment of the invention,the compound of formula XXX is first treated with the base at roomtemperature in a low boiling ether solvent such as tetrahydrofuran. Theresulting salt of the compound of formula XXX can, if desired, beisolated and reacted with the compound of formula XXXI at reflux, in ahigher boiling inert organic solvent such as acetonitrile.

The compound of formula XXXII is converted to the compound of formulaIV-D via the following intermediates: ##STR25## wherein R₁₅ and R₁₉ areas above.

The compound of formula XXXII is converted to the compound of formulaXXXIII by first treating the compound of formula XXXII with a base suchas the alkali metal hydrides or alkali metal hydroxides and thenreacting the basic salt thus formed with a fluorinating agent such asperchloryl fluoride. This reaction is preferably carried out under aninert gaseous atmosphere such as argon. This reaction produces thecompound of formulae XXXIII and XXXIV in admixture. This mixture can, ifdesired, be separated by conventional means such as chromatography. Incarrying out the reaction whereby the compound of formula XXXII isconverted to the compound of formula XXXIII and XXXIV, both theformation of the salt and the treatment with a fluorinating agent can becarried out in an inert organic solvent. Any conventional inert organicsolvent can be utilized in carrying out these reactions. Among thepreferred solvents are the hydrocarbon solvents such as toluene,benzene, etc. In carrying out the reaction, any conventionalfluorinating agent, such as perchloryl fluoride, can be utilized. Thereaction with the perchloryl fluoride or other conventional fluorinatingagents is generally carried out at very low temperatures, -30° to 0° C.On the other hand, formation of the salt of the compound of formulaXXXII is carried out at room temperature. In fact, any temperature offrom 0°-50° C. can be utilized in forming this salt.

The compound of formula XXXIV can be converted to the compound offormula IV-D by hydrolysis in the presence of an aqueous alkali metalhydroxy such as sodium hydroxide. In general, any of the conditionsconventional in hydrolysis with an alkali metal aqueous base can beutilized in carrying out this conversion. On the other hand, thecompound of formula XXXIII can be hydrolyzed by first treating thecompound of formula XXXIII with an alkali metal lower alkoxide in aninert organic solvent to convert the compound of formula XXXIII to thecompound of formula XXXIV and thereafter hydrolyzing the compound offormula XXXIV with an aqueous alkali metal hydroxide to convert thecompound of formula XXXIV with the compound of formula IV-D. Thetreatment with an alkali metal lower alkoxide can be carried out in theconventional manner utilizing an inert organic solvent, such as thelower alkanol solvents, particularly methanol ethanol, isopropanol, etc.

On the other hand, the mixture containing the compounds of formulaeXXXIII and XXXIV need not be separated, but can be converted to thecompound of formula IV-D by first treatment with an aqueous alkali metalalkoxide and then with an aqueous alkali metal lower hydroxide in theaforementioned manner.

The compound of formula I where R is --COOR₂₀ and R₂₀ is lower alkyl canbe prepared from the corresponding compound of formula I where R is--COOH or ##STR26## by esterification with a lower alkanol in thepresence of a strong acid. Any conventional method of esterification canbe utilized to carry out this reaction.

The compound of formula II can be prepared by reacting a compound of theformula ##STR27## with a compound of the formula IV-A in the same manneras described hereinbefore in connection with the reaction of a compoundV with the compound of the formula IV. This reaction produces a compoundof the formula: ##STR28##

This compound can be hydrolyzed by treatment with an aqueous mineralacid as described in the conversion of a compound of formula I-B to I-Cto produce the compound of the formula: ##STR29## wherein Δ is as above.

The compound of formula II-C can be esterified with a lower alkanol inthe manner described hereinbefore in connection with the esterificationof a compound of formula I where R is COOH, to produce a compound of theformula: ##STR30## where R₂₀ is lower alkyl and Δ is as above. In thecompounds of formula II, the double bonds have this cis configuration.

The compounds of formulae I and II where R is --COOH can be converted totheir salts by conventional salt formation. Any conventional means ofconverting a free acid into a salt can be utilized in formingpharmaceutically acceptable basic salts of compounds of the formula Iand II.

In all of the reactions described above which involve a compoundcontaining a triple bond in either a reactant or a product, it isgenerally preferred to carry out this reaction under an inert gaseousatmosphere. Any conventional inert gas such as those mentionedhereinbefore can be utilized in carrying out these reactions involving acompound containing a triple bond as a reactant or as a product.

The invention is further illustrated by the following examples. In theexamples, all temperatures are in degrees Centigrade. Ether, as utilizedin these examples, refers to diethyl ether. The term "mm" refers tomillimeters of mercury. Unless specified, all percents are percents byweight. In the Examples, "THF" designates tetrahydrofuran.

EXAMPLE 1 4-Pentyn-1-al

A mixture of 4-pentyn-1-ol(13.5 g, 16.05 mmol), pyridiniumchlorochromate (51.9 g, 24.07 mmol), and sodium acetate (4.34 g, 5.29mmol) in CH₂ Cl₂ (200 ml) was stirred at 25° C. for 2.5 h. Ether wasadded and the mixture was filtered over about 50 g of celite and washedwell with ether. After evaporation of ether on a rotary evaporator at30° C./>100 mmHg, the resulting crude material was distilled to give 7.3g (55%) of 4-pentyn-1-al as a colorless liquid, bp 65°-68° C./65 mm(Lit. bp 70°/50 mmHg).

EXAMPLE 2 2[(Methylsulfonyl)oxy]-5-hexynenitrile

A solution of sodium bisulfite (8.62 g, 82.8 mmol) in 20 ml of water wasadded at 0° C., to a mixture of 4-pentyn-1-al (6.8 g, 82.8 mmol) in 10ml of water. The reaction mixture was stirred at 0° C. for 1/2 hr. Asolution of sodium cyanide (4.05 g, 82.8 mmol) in 30 ml of water wasthen added portionwise and the mixture was further stirred at 0° C. for1.0 h. It was extracted three times with ether. The combined etherextracts were washed with brine, dried over Na₂ SO₄, and filtered. Theether was concentrated at 35° C./80-100 mm to give 8.07 g of2-hydroxy-5-hexynenitrile as a colorless liquid which was used directlyfor the next step described below.

A mixture of 2-hydroxy-5-hexynenitrile (8.0 g, 73.3 mmol) and drytriethylamine (10.1 g, 0.1 mol) in 50 ml of dry CH₂ Cl₂ was treated witha solution of methanesulfonyl chloride (10.3 g, 90 mmol) in 50 ml of CH₂Cl₂, at 0° C. for 11/2 h. The reaction mixture was diluted with CH₂ Cl₂,washed twice with cold 1.0 N H₂ SO₄, twice with water, and dried overMgSO₄. The filtered CH₂ Cl₂ solution was concentrated at 40° C./30 mm togive 12 g of pale yellow liquid. Purification of this material on 220 gof silica gel and eluted with ether-petroleum ether (1:1 parts byvolume) gave 8.7 g (56% by weight yield from pentynal) of2-[(methylsulfonyl)]-5-hexynenitrile as a colorless liquid.

EXAMPLE 3 2-Fluoro-5-Hexynoic Acid

A mixture of 2-[(methylsulfonyl)oxy]-5-hexynenitrile (7.7 g, 41.1 mmol)and dry potassium fluoride (3.57 g, 61.4 mmol) in 10 ml of drydiethylene glycol was heated with vigorous stirring, at 135° C. underargon for 2 h. The resulting black reaction mixture was taken into 50 mlof water and extracted with ether (3×25 ml). The combined ether extractswere washed with water and then treated with a solution of potassiumhydroxide (2.3 g, 61.4 mmol) in 15 ml of water. The resulting mixturewas heated with stirring, at 65° C. (bath) for 2.0 h. The ether wasdistilled off at one atmosphere, and the aqueous solution was cooled toabout 25° C., diluted with 50 ml of ice-water, and extracted with ether(3×50 ml). The ether extracts were combined and extracted with 2×50 mlin NaOH solution. The combined NaOH solution was cooled to 0° C. andthen acidified to pH 2.5 with cold 3 N H₂ SO₄ solution. The resultingacidic aqueous phase was extracted with three times ether. The etherextracts were combined, washed with water, and dried (MgSO₄).Concentration of ether at 40° C./˜±mm, and evaporative distillation ofthe resulting crude product at 130°/10 mmHg afforded 1.75 g (33% byweight yield) of 2-fluoro-5-hexynoic acid as a colorless liquid whichsolidified on cooling to a temperature of -10° C. to -20° C. as a whitesolid.

EXAMPLE 4 2-(1-Fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole

A mixture of 2-fluoro-5-hexynoic acid (3.0 g, 23.05 mmol) and2-amino-2-methyl-1-propanol (2.05 g, 23.05 mmol) in 150 ml of dry xylenewas refluxed for 16 h. The water formed during the reaction was removedby Linde 3A molecular sieves (15 g) contained in a continuous extractor.The xylene was then distilled off at atmospheric pressure, and theresulting pot material was taken into ether (100 ml). The etherealsolution was washed with saturated sodium bicarbonate solution, water,and dried over MgSO₄. Evaporation of ether at 35° C./˜35 mm, anddistillation of the resulting crude product gave 2.4 g (57%) of2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole as a colorlessliquid, bp 62°-66° C./0.6 mmHg. EXAMPLE 5

2-(1-Fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

A solution of ethyl magnesium bromide in THF (0.98 ml, 1.86 N) was addeddropwise at 25° C., under argon, to a stirred solution of2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole (348 mg, 1.9mmol) in THF (1 ml). The resulting reaction mixture was stirred at 25°C. under argon for 2.0 h. Copper (I) cyanide (18 mg, 0.2 mmol) was addedand the mixture was stirred for 1/4 h. A solution of(Z)-1-bromo-8-tetradecen-2-yne (500 mg, 1.84 mmol) in dry THF (1 ml) wasthen added dropwise and the resulting reaction mixture was stirred at25° C. for 2 h, and was further refluxed for 3 h under argon. Themixture was cooled in an ice bath, diluted with water (100 ml), andextracted three times with ether. The combined ether extracts werewashed with water, dried over MgSO₄, filtered, and concentrated at 35°C./˜ 35 mm. The crude oily product was purified by flash chromatographyon silica gel (60 g) and eluted with ethyl acetate-petroleum ether (1:4parts by volume) to yield 311 mg (45% by weight yield) of2-(1-fluorononadec-13(Z)en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazoleas a colorless oil.

EXAMPLE 6 (Z)-2-Fluoro-1,4-Eicosene-5,8-diynoic acid

A suspension of2-(1-fluorononadec-13-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole (86mg) in 3 ml of 3 N HCl was refluxed with stirring under argon for 15min. It was cooled to about 23° C., diluted with 3 ml of water, andextracted three times with ether. The ether extracts were combined,washed with brine, and dried over MgSO₄. Concentration of ether at 35°C./35 mmHg gave the crude acid which was purified by flashchromatography on silica gel (8 g, 230-400 mesh). Elution with HOAc-CH₃OH--CHCl₃ under nitrogen afforded 49 mg (66% yield by weight) of(Z)-2-fluoro-14-eicosene-5,8-diynoic acid as a colorless oil.

EXAMPLE 72-[(Z)-13-Nonadecen-4,7-diynyl]-4,5-dihydro-4,4-dimethyloxazole

In a similar manner as described above in Example 5 for the preparationof2-[1-fluorononadec-13(Z)-en-4,7-diynyl)]-4,5-dihydro-4,4-dimethyloxazole,2-[(Z)-13-nonadecen-4,7-diynyl]-4,5-dihydro-4,4-dimethyloxazole wassynthesized from (Z)-1-bromo-8-tetradecen-2-yne and2-(4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole.

EXAMPLE 8 Preparation of 2-Acetyl-6-(trimethylsilyl)-5-hexynoic acidethyl ester

Ethyl aceteoacetate (11.6 g) was added dropwise to an ice-cooledsuspension of sodium hydride (2.0 g) in tetrahydrofuran (150 ml) under apositive argon atmosphere After stirring for 30 minutes, the reactionmixture was allowed to stand until the solids had settled. The clearsolution was removed via a transfer needle and then condensed by rotaryevaporation to yield an off-white solid. This material was mixed withacetonitrile (150 ml) and heated to reflux under a postive argonatmosphere as 4-iodo-1-butynyltrimethylsilane (16.0 g) was added. Thereaction mixture was heated to reflux for 21 hours. The volatiles wereremoved by rotary evaporation and the residual material partitionedbetween hexane and dilute hydrochloric acid. The hexane layer was washedwith sat. sodium bicarbonate solution, dried (MgSO₄) and condensed byrotary evaporation to yield an oil. This material was vacuum distilledto give 8.24 g of 2-acetyl-6-(trimethylsilyl)-5-hexynoic acid ethylester; bp 97°-101°/0.005 mmHg.

EXAMPLE 9 Preparation of 2-Acetyl-2-Fluoro-6-(Trimethylsilyl)-5-hexynoicAcid ethyl ester and 2-Fluoro-6-(trimethylsilyl)-5-hexynoic acid ethylester

2-acetyl-6-(trimethylsilyl)-5-hexynoic acid ethyl ester (7.1 g) wasadded to a suspension of sodium hydride (1.0 g) in toluene under apositive argon atmosphere. After stirring for 1 hour, the reactionmixture was cooled to -10° and a mixture of perchloryl fluoride andargon gases was bubbled through the reaction mixture at such a rate thatthe internal temperature never exceeded 0° C. The perchloryl fluorideaddition was discontinued when it ceased to be exothermic. Argon wasbubbled through the mixture as it was allowed to warm to roomtemperature. The reaction mixture was partitioned between hexane andwater and the organic phase was dried (MgSO₄) and condensed by rotaryevaporation to give an oil. The components of the oil were separated bysilica gel chromatography using 30% ethyl acetate/hexane as the eluantto give 5.9 g of 2-acetyl-2-fluoro-6-(trimethylsilyl)-5-hexynoic acidethyl ester. There was also obtained 0.25 g of2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester.

EXAMPLE 10 Preparation of 2-Fluoro-5-Hexynoic Acid

To a solution of 2-acetyl-2-fluoro-6-(trimethylsilyl)-5-hexynoic acidethyl ester (6.63 g) in ethanol (20 ml) was added 27 ml of 2.65 M sodiumethoxide/ethanol. After 18 hours, 7 ml of 4 N sodium hydroxide wasadded. After 6 hours, the solvent was removed by rotary evaporation andthe residual materials partitioned between ethyl ether and dilutehydrochloric acid. The organic layer was dried (MgSO₄) and the solventremoved by rotary evaporation to give an oil which was vacuum distilledto yield 3.2 g of 2-fluoro-5-hexynoic acid; b.p. 118°/14 mmHg.

EXAMPLE 11 (Z,Z)-2,5-Undecadien-1-ol

2,5-undecadiyn-1-ol (1.5 g) in absolute ethanol (15 ml) was reduced withLindlar catalyst (0.33 g) in the presence of quinoline (0.1 ml) at 25°C., 1 atm., for 7 h. The uptake of hydrogen stopped at 420 ml(theoretical 428 ml). The solution was filtered, and the solvent wasevaporated to give 1.5 g of crude product which was then purified bycolumn chromatography on silica gel (50 g). Elution with ether-petroleumether (1:4 parts by volume) gave 1.07 g of (Z,Z)-2,5-undecadien-1-ol asan oil.

EXAMPLE 12 (Z,Z)-1-Chloro-2,5-undecadiene

A mixture of (Z,Z)-undecadien-1-ol (3.42 g, 20.4 mmol) andtriphenylphosphine (7.5 g, 28.6 mmol) in dry CCl₄ (25 ml) was refluxedwith stirring for 9 h. The reaction mixture was allowed to cool to 23°C., hexane (60 ml) was added, and stirring was continued for anadditional 10 minutes. The precipitate of triphenylphosphine oxide wasfiltered and washed with hexane. The solvent was removed from thecombined filtrate at 40° C./˜30 mmHg. Evaporation distillation of theresulting residue at 125°-130° C./0.3 mmHg gave 3.5 g (92%) of(Z,Z)-1-chloro-2,5-undecadiene as a colorless liquid.

EXAMPLE 13 (Z,Z)-5,8-Tetradecadien-2-yn-1-ol

A solution of ethylmagnesium bromide in THF (10 ml) was prepared frommagnesium (1.4 g, 57.7 mmol) and ethyl bromide (7.7 g, 71 mmol).Propargyl alcohol (1.53 g, 27.4 mmol) in dry THF (6 ml) was then addeddropwise to the above ethylmagnesium bromide solution at 5° C. withvigorous stirring. The resulting viscous mixture was stirred at 23° C.under argon for twenty minutes. Cuprous chloride (0.14 g) was added andthe reaction mixture was further stirred for twenty minutes. A solutionof (Z,Z)-1-chloro-2,5-undecadiene (3.4 g, 18.2 mmol) in THF (2.0 ml) wasthen added dropwise to the above mentioned mixture over a period oftwenty five minutes, at 20° C. The reaction mixture was stirred at 50°C. under argon for 18 h. The THF was removed at ˜35° C. on a rotaryevaporator and the resulting residue was treated with cold 1.5 N H₂ SO₄(150 ml). It was extracted with ether, washed with water, and dried overNa₂ SO₄. Evaporation of ether at reduced pressure gave 3.7 g of lightyellow oil which was chromtographed on 70 g of silica gel. Elution withether-petroleum ether (1:3) gave 2.3 g (61%) of(Z,Z)-5,8-tetradecadien-2-yn-1-ol which was evaporatively distilled at137°-140° C./0.3 mmHg as a colorless liquid.

EXAMPLE 14 (Z,Z)-1-Bromo-5,8-tetradecadien-2-yne

A solution of phosphorous tribromide (0.47 g, 1.73 mmol) in absoluteether (0.5 ml) was added dropwise during five minutes to a mixture of(Z,Z)-5,8-tetradecadien-2-yn-1-ol (1.03 g, 5 mmol), and dry pyridine (14mg, 0.18 mmol) in 8 ml of absolute ether. The reaction mixture washeated under reflux for 2.5 h, cooled to 23° C., then poured ontoice-water. It was extracted three times with ether. The combined etherextracts were washed with dilute aqueous sodium bicarbonate solution,water, dried over Na₂ SO₄ and concentrated in vacuo. Evaporativedistillation of the crude product at 145°-148° C./0.15 mm afforded 1.1 g(80.5%) of (Z,Z)-1-bromo-5,8-tetradecadien-2-yne as a pale yellow oil.

EXAMPLE 15 (Z,Z)-11,14-Eicosadien-5,8-Diynoic Acid

A solution of 5-hexynoic acid (0.73 g, 6.5 mmol) in dry THF (2 ml) wasadded dropwise at 4° C., under argon, to a vigorously stirred mixture ofethylmagnesium bromide (prepared from 0.32 g, 13.2 mg-atom of magnesium,and 2.04 g, 18.7 mmol of ethyl bromide) in 5 ml of dry THF. The reactionmixture was then stirred at 23° C. under argon for 1.5 h. Cuprouscyanide (40 mg, 0.45 mmol) was added and the mixture was further stirredfor 10 min. A solution of (Z,Z)-1-bromo-5,8-tetradecadien-2-yne (0.58 g,2.0 mmol) in 2 ml of dry THF was then added dropwise at 23° C. underargon. The resulting reaction mixture was stirred at 23° C. under argonfor 20 h. It was poured into cold 2 N H₂ SO₄ and extracted three timeswith ether. The combined ether extracts were extracted three times with1 N NH₄ OH solution. Acidification of the combined ammonia hydroxidesolution to pH 3, followed by isolation of the product by the usualether extraction procedure gave 0.98 g of crude acidic product.Evaporative distillation of this material at 75°-84° C./0.15 mmHg gave0.14 g of 5-hexynoic acid. The pot residue (0.81 g) was chromatographedon 40 g of silica gel (silica gel 60, 230-400 mesh) under a slightpressure of nitrogen. Elution with ether-petroleum ether (2:3 parts byvolume) gave 0.33 g (55% yield based on bromide) of(Z,Z)-11,14-eicosadien-5,8-diynoic acid as a pale yellow oil.

EXAMPLE 16 (Z,Z)-11,14-Eicosadien-5,8-Diynoic Acid Methyl Ester

Treatment of (Z,Z)-11,14-eicosadien-5,8-diynoic acid with diazomethanein ether at 4° C. for 0.5 h gave the corresponding methyl ester as apale yellow oil: bp 160°-175° C./0.01 mmHg (evaporative distillation).

EXAMPLE 17 (Z)-5-Undecen-1-ol

A mixture of n-hexyltriphenylphosphonium bromide (75 g, 0.175 mmol) andsodium bistrimethylsilylamide (31.5 g, 0.17 mol) in dry THF (400 ml) wasstirred at 23° C. under argon for 3 h. To the resulting bright orangesuspension, a solution of 5-hydroxypentanal (8.04 g, 78 mmol) in 25 mlof dry THF was added. The reaction mixture was stirred at 23° C. underargon for 3.0 h. The THF was evaporated at reduced pressure and theresulting residue was treated with 200 ml of water and extracted threetimes with ether. The combined ether extracts were washed with water,dried over anhydrous Na₂ SO₄, and evaporated at reduced pressure to give21.8 g of pale yellow oil after a quick chromatography on 400 g ofsilica gel using ether-petroleum ether (1:1 parts by volume) as eluent.Distillation of this material gave 11.4 g (80% by weight yield based onaldehyde) of (Z)-5-undecen-1-ol as a colorless liquid: bp 101°-102°C./15 mmHg.

EXAMPLE 18 (Z)-1-Bromo-5-Undecene

A solution of phosphorous tribromide (2.09 g, 7.8 mmol) in dry ether (2ml) was added dropwise, at 25° C., to a mixture of (Z)-5-undecen-1-ol(4.24 g, 23.1 mmol), and pyridine (79 mg, 1 mmol) in 25 ml of dry ether.The resulting reaction mixture was heated under reflux with stirringunder argon for 2 h. It was cooled to 23° C., poured onto water (100ml), and extracted three times with ether. The ether extracts werecombined, washed two times each with saturated aqueous sodiumbicarbonate solution, water, and dried over anhydrous Na₂ SO₄.Evaporation of ether to dryness at reduced pressure yielded 3.8 g ofmaterial. This was filtered over 35 g of silica gel and eluted withether-petroleum ether (2:3 parts by volume). The fractions containingthe desired product were combined and the solvent was evaporated atreduced pressure. The resulting residue was purified by evaporativedistillation at 105°-110° C./0.2 mmHg to give 2.73 g (51% by weightyield) of (Z)-1-bromo-5-undecene as a colorless liquid.

EXAMPLE 19 1-(Tetrahydro-2-pyranoxy)-(Z)-8-tetradecen-2-yne

A solution of n-butyllithium (11.5 ml, 27.3 mmol) in hexane was addeddropwise, under an argon atmosphere, over a period of 10 minutes to asolution of 1-(tetrahydro-2-pyranoxy)-2-propyne (3.83 g, 27.3 mmol) in30 ml of dry THF, while the temperature of the reaction mixture was keptbelow 10° C. To the resulting yellow lithium acetylide solution, asolution of (Z)-1-bromo-5-undecene (6.07 g, 27.3 mmol) in 30 ml of dryhexamethylphosphoric triamide (HMPA) was added at 4° C. The reactionmixture was stirred at 23° C. under argon for 1.0 h, and then pouredinto ice-water (100 ml). It was extracted three times with ether. Thecombined ether extracts were washed with brine, dried over anhydrous Na₂SO₄, and evaporated at reduced pressure to give 8.0 g of product. Thismaterial was quickly filtered over 40 g of silica gel. Elution withether-petroleum ether (2:3 parts by volume) gave 6.6 g (83% by weightyeild) of 1-(tetrahydro-2-pyranoxy)-(Z)-8-tetradecen-2-yne as a paleyellow oil, which was used directly for the next step described below.

EXAMPLE 20 (Z)-8-Tetradecen-2-yn-1-ol

A mixture of 1-(tetrahydro-2-pyranoxy)-(Z)-8-tetradecen-2-yne (6.2 g,21.2 mmol) and p-toluenesulfonic acid (0.46 g) in 50 ml of methanol wasstirred at 23° C. under argon for 1.0 h. Solid sodium carbonate (2 g)was added and the mixture was stirred for an additional fifteen minutes.It was filtered, washed with methanol, and concentrated to nearlydryness. The resulting oily residue was taken into ether, washed withwater, and dried over anhydrous Na₂ SO₄. Evaporation of ether in vacuogave an oily material which was passed through a column of 35 g ofsilica gel and eluted with ether-petroleum ether (1:1 parts by volume)to yield 4.2 g of pale yellow oil. Evaporative distillation of thismaterial at 90° C./0.2 mmHg afforded 3.8 g (85% by weight yield) of(Z)-8-tetradecen-2-yn-1-ol as a colorless oil.

EXAMPLE 21 (Z)-1-Bromo-8-tetradecen-2-yne

By the procedure of example 14, 3.82 g (18.34 mmol) of(Z)-8-tetradecen-2-yn-1-ol, 72 mg of dry pyridine, and 1.66 g (6.12mmol) of phosphorous tribromide were reacted in 20 ml of ether underreflux for 2.0 h. It was worked up as described in example 14 to give3.83 g of crude product. It was purified by evaporative distillation at105° C.-120° C./0.25 mm to yield 3.64 g (73% by weight yield) of(Z)-1-bromo-8-tetradecen-2-yne as a colorless oil.

EXAMPLE 22 (Z)-14-Eicosen-5,8-diynoic acid

By the procedure of example 15, the di-Grignard complex of 5-hexynoicacid (213 mg, 1.9 mmol) was prepared from magnesium (93 mg, 4.0 mmol)and ethyl bromide (458 mg, 4.2 mmol) in 3 ml of dry THF. To this mixturecuprous cyanide (18 mg, 0.2 mmol) was added and stirring was continuedfor 10 min. A solution of (Z)-1-bromo-8-tetradecen-2-yne (540 mg, 2.0mmol) in THF (2 ml) was then added dropwise. The reaction mixture wasstirred at 23° C. under argon for 18 h, and was further heated underreflux for 5 h. Work up of the reaction mixture and purification of thecrude product as described in example 15 gave 326 mg of(Z)-14-eicosen-5,8-diynoic acid as a pale yellow oil.

EXAMPLE 23 (Z)-2-Undecen-1-ol

A mixture of 2-undecyl-1-ol (15 g), quinoline (0.6 ml), and 9 g ofLindlar catalyst was hydrogenated at 23° C., 1 atm until the uptake ofhydrogen was complete. The catalyst was filtered off and washed withhexane. The hexane solution was washed with 1 N HCl solution, brine, anddried over anhydrous Na₂ SO₄. Concentration of solvent in vacuo anddistillation of the resulting residue gave 13.3 g of (Z)-2-undecen-1-olas a colorless oil: bp 77°-80° C./0.1 mmHg.

EXAMPLE 24 (Z)-1-Chloro-2-undecene

By the procedure of example 12, (Z)-2-undecen-1-ol (13 g), 27.8 g oftriphenylphosphine in 100 ml of dry CCl₄ were reacted under reflux for6.5 h. Workup as described before as in example 12 gave 12.3 g of(Z)-1-chloro-2-undecene as a colorless oil: bp 65°-66° C./0.2 mmHg.

EXAMPLE 25 (Z)-5-Tetradecen-2-yn-1-ol

By the procedure of example 13, (Z)-1-chloro-2-undecene (4.0 g, 21mmol), the Grignard complex of propargyl alcohol (prepared from 35 mmolof propargyl alcohol and 70 mmol of ethylmagnesium bromide in 35 ml ofdry THF), and 252 mg of CuCl were allowed to react at 50° C. for 20 h.under argon. Workup of the reaction mixture and purification of thecrude product as described before in example 13 gave 2.54 g (58% byweight yield) of (Z)-5-tetradecen-2-yn-1-ol as a colorless oil, bp102°-127° C./0.25 mmHg (evaporative distillation).

EXAMPLE 26

By the same procedure of example 14, (Z)-5-tetradecen-2-yn-1-ol wasconverted to (Z)-1-bromo-5-tetradecen-2-yne.

EXAMPLE 27 (Z)-11-Eicosen-5,8-diynoic acid

By the same procedure of example 22, (Z)-1-bromo-5-tetradecen-2-yne, andthe Grignard complex of 5-hexynoic acid gave (Z)-11-eiconsen-5,8-diynoicacid.

EXAMPLE 282-[1-Fluorononadeca-7(Z),10(Z),13(Z)-trien-4-ynyl]-4,5-dihydro-4,4-dimethyloxazole

A solution of 2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole(1.09 g, 6.0 mmol) in 2 ml of dry THF was treated, dropwise, at 0° C.,under argon, with 2.26 ml (2.65 N in THF) of ethylmagnesium bromide. Theresulting mixture was stirred at 25° C. under argon for 2 h. Copper Icyanide (54 mg) was then added, and the mixture was stirred at 25° C.for 15 min. A solution of 1-chloro-2(Z),5(Z),8(Z)-tetradecatriene (544mg, 2.4 mmol) in a small amount of dry THF was added. The reactionmixture was stirred at 25° C. for 2 h, and then at 40° C. for 10 h underargon. Water was added and the mixture was extracted with ether. Theether extracts were combined, washed with water, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo. The crude product waspurified by flash column chromatography on 120 g of silica gel. Elutionwith CH₂ Cl₂ -ether (19:1) gave 171 mg of2-[1-fluorononadeca-7(Z),10(Z),13(Z)-trien-4-ynyl]-4,5-dihydro-4,4-dimethyloxazoleas a colorless oil.

EXAMPLE 29 2-Fluoro-8(Z),11(Z),14(Z)-eicosatrien-5-ynoic acid

2-[1-fluorononadeca-7(Z),10(Z),13(Z)-trien-4-ynyl]-4,5-dihydro-4,4-dimethyloxazolewas hydrolyzed in refluxing 3 N HCl for 15 min. as described in Example6, to give 2-fluoro-8(Z),11(Z),14(Z)-eicosatrien-5-ynoic acid as acolorless oil.

In Examples 30-33, the compounds of this invention were tested against5,8,11,14-eicosatetraynoic acid and 9,12-octadecdiynoic acid. Thecompound 5,8,11,14-eicosatetraynoic acid is standard potent inhibitor ofSRS-A synthesis as well as of Δ¹² -lipoxygenase and prostaglandinendoperoxide synthase. On the other hand, the 9,12-octadecadiynoic acidis also a potent standard inhibitor of SRS-A synthesis and prostaglandinendoperoxide synthase while not being an inhibitor of Δ¹² lipoxygenase.

The compounds tested were as follows:

Compound 3. (Z,Z)-11,14-eicosadien-5,8-diynoic acid.

Compound 4. (Z,Z)-11,14-eicosadien-5,8-diynoic acid methyl ester.

Compound 5. (Z)-11-eicosen-5,8-diynoic acid.

Compound 6. (Z)-14-eicosen-5,8-diynoic acid

Compound 7.2[(Z)-13-nonadecen-4,7-diynyl]-4,5-dihydro-4,4-dimethyloxazole.

Compound 8.2-(1-fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole.

EXAMPLE 30 Inhibition in the In Vitro Synthesis of SRS-A in RatPeritoneal Cells

To study the effect of drugs on SRS-A synthesis in rat peritoneal cells,these cells (including mast cells, monocytes, eosinophils andneutrophils) were isolated from male Spague-Dawley rats (Charles RiverLaboratories) weighing 180-220 g by the lavage procedure described byHerzig, D. J. and Kusner, E. J., Journal of Pharmacology andExperimental Therapeutics, 194, 457-462 (1975) with the exception thatHanks balanced salt solution used in these experiments was adjusted topH 6.9 with 5% (V/V) of 0.1 M aqueous phosphate buffer and contained 50mg/ml sodium heparin. After removal from the peritoneal cavity of rats,the cells were subsequently isolated by centrifugation at 400×gravityfor 10 minutes at 4° C. and resuspended to a concentration of about2,000,000 cells per ml in Hanks buffer.

Samples for evaluation were prepared by adding various concentrations oftest drugs to 2 ml aliquots of the resuspensed cells in Hanks buffer.The 2 ml samples used for control contained 2 ml aliquots of resuspendedcells in Hanks buffer without drugs. All of the above samples (2 mlfinal volume) were preincubated at 37° C. for 10 minutes in the presenceof varying concentrations of test drug prior to challenge with 5×10⁻⁷ Mionophore A23107. This ionophore is disclosed in Burka and Flower, Br.J. Pharmacology 65:35-41 (1979). Antibiotic A23187 was used as a probefor the study of calcium and magnesium function in biological systems.After ionophore challenge, SRS-A was synthesized in the samples by thecells for 10 minutes (at 37° C.) after which this synthesis wasterminated by placing the samples in a boiling water bath for 10 minutesfollowed by centrifugation at 2,000×g (10 minutes) at 4° C. to removecoagulated protein and cellular debris. The SRS-A present in theresulting supernatants was quantitated by a bioassay using a guinea pigileum as described in Orange, and Austen, Adv. Immunol. 10:105-144 144(1969). For this bioassay, a 1.5 cm segment of ileum was removed fromanimals weighing 300 to 400 g and suspended in an organ bath containing10 ml of Tyrodes solution with 10⁻⁶ M atropine sulfate and 10⁻⁶ Mpyrilamine maleate. The bath was maintained at 37° C. and aereated witha mixture of 95% O₂ and 5%CO₂. The concentration of SRS-A in theexperimental samples was determined by a comparison of the isotoniccontraction responses elicited by the samples with those obtained withvarying amounts of an SRS-A standard solution prepared from choppedguinea pig lung as disclosed in Hitchcock, M. J. Pharmacol. Exp. Ther.207: 630-640 (1978) and quantituted by the procedures of Orange, R. R.and Austen, K. F. Adv. Immunol. 10:105-144 (1969) against histamine (1unit of SRS-A being that amount which gives a contractile responsesimilar to that of 5 μg of histamine). In the absence of drug, theionophore A23187-induced SRS-A synthesis varied between 40 to 50 unitsof SRS-A per 10⁶ cells. In the presence of increasing concentrations oftest drug, there was a concentration-related decrease in SRS-Asynthesis.

The mean percent inhibition= ##EQU1## at each concentration of thevarious test drugs was calculated. The concentration of test drug whichinhibits the synthesis of SRS-A by 50% (IC₅₀) was determined for eachtest drug from a plot of the mean percent inhibition versus the log ofdrug concentration. Both the % inhibition at 10 μM and the IC₅₀ aregiven in the following table. The difference of units of SRS-A in thetest sample used in the fraction given above was obtained bysubstracting from the units of SRS-A in the control from the actualmeasurement of the units of SRS-A in the sample.

EXAMPLE 31 Assays for Δ¹² -Lipoxygenase

Δ¹² -lipoxygenase activity was measured by following the conversion of¹⁴ C-arachidonic acid (AA) to ¹⁴ C-12-hydroxy-5,8,10,14-eicosatetraenoicacid (12-HETE) using human platelets as the enzyme source. Washed humanplatelets from approximately 2000 ml of blood were suspended in 50 ml ofphosphate buffered saline (PBS) and then lysed by freezing and thawing(3 times). The platelet lysate was homogenized using a glass-teflonhomogenizer and then particulate material was sedimented bycentifugation at 100,000×g for 1 hr and the sediment was discarded. Thesupernatant was made 50% by weight saturated with respect to (NH₄)₂ SO₄by adding solid ammonium sulfate. The resultant suspension was allowedto stand at 0° overnight. The precipitate was collected bycentrifugation and was dissolved in approximately 25 ml of PBS. Thissolution was the enzyme solution utilized to catalyze the conversion ofAA to 12 HETE.

In order to test the compounds, separate incubation tubes for each ofthe compounds and for concentrations of these compounds were prepared inan ice bath. These tubes each contained 140 μl of PBS containing 1.78 mMglutathione, 10 μl of test drug in ethanol, 50 μl of plateletsupernatant, and 50 μl of ¹⁴ C-AA. Incubation tubes used as the enzymecontrol did not contain any test compound but rather contained 10 μl ofethanol. Incubation tubes were prepared containing only buffer ethanoland ¹⁴ c-AA were included as substrate controls. The final concentrationof AA added as its ammonium salt in PBS, in each of the incubation tubeswas 3-4 μM. Sufficient enzyme solution prepared as above was added sothat, under the conditions of the assay, approximately 80-90% by weightof the ¹⁴ C-AA was converted to 12-HETE, as determined by priorcontrols. The tubes were incubated at 37° for 2 min, the reaction wasstopped by the addition, while mixing on a mixer, of 2 ml of diethylether and 50 μl of 1 M citric acid. The ether in the presence of citricacid extracted 12-HETE and AA from enzyme in the reaction medium in eachof the samples. The ether extract was evaporated to dryness undernitrogen and then the residue was dissolved in 50 μl ofchloroform:methanol (2:1 parts by volume). The dissolved residuecontaining 12-HETE and AA was applied, as rapidly as possible, to aglass fiber sheet impregnated with silica gel and then the chromatogramwas developed using isooctane:methylethylketone:acetic acid (100:9:1parts by volume) as solvent. Radioactive products and unconverted ¹⁴C-AA were located using a thin-layer chromatography scanner. Theappropriate regions of the chromatogram were cut out, then theradioactivity quantitated using a liquid scintillation counter. Theamount of ¹⁴ C-AA converted to product is used as a measure of Δ¹²-lipoxygenase activity.

The mean percent inhibition was calculated by multiplying 100 times thefollowing fraction: ##EQU2## at each concentration of the various testdrugs was calculated. The concentration of test drug which inhibits theconversion of 14-AA to 12-HETE by 50% (IC₅₀) was determined for eachtest drug from a plot of the mean percent inhibition versus log of drugconcentration. This result is given in the following table.

EXAMPLE 32 Prostaglandin Endoperoxidesynthase (PES)

The activity of PES was measured polarigraphically by following thedisappearance of dissolved O₂ from incubation mixtures containingarachidonic acid (AA) as substrate and sheep seminal vesicular glandmicrosomes (SSVM) as the enzyme source. Fifty mg of an acetone powder ofSSVM were suspended, using a glass teflon homogenizer, in 1 ml of 0.1 Mtris. HCl (pH, 8.5) containing 0.67 mM phenol. This suspension of SSVMwas incubated at room temperature in the presence of phenol to maximumlyactivate the PES and then the suspension was kept at 0°.

Samples in a separate reaction vessel were each prepared by addingtris-phenol buffer (2.8 ml), 0.05 ml of the SSVM suspension, and amaximum of 0.12 ml of ethanol containing various concentrations of thetest drug. The controls were prepared in the same manner except that theethanol added did not contain any test drug. Reaction vessels were thenallowed to reach temperature equilibrium. An oxygen electrode isinserted into the vessel and then 24 μl of 4.1 mM AA are injected intothe sealed vessel through a port on the side of the electrode. The finalconcentration of AA is 33 μM. Oxygen uptake is recorded and the initialrate of oxygen uptake used as a measure of PES activity. Each of thetest compounds were tested initially at a high concentration (1 mM) andthen, if required, dilutions are made.

The mean percent inhibition was obtained for each concentration of thevarious test drugs by expressing as a percent the number obtained bydividing the difference of the oxygen uptake of the test sample by theoxygen uptake of the control. The concentration of test drug whichinhibits the synthesis of PES by 50% (IC₅₀) which is given in thefollowing table was determined for each test drug from a plot of meanpercent inhibition verses drug concentration. The difference of theoxygen uptake of test sample was obtained by subtracting from the oxygenuptake of the control, the oxygen uptake of the test sample.

The results of the tests of Examples 30 through 32 with respect to thecompounds of this invention are given in the foregoing Table. As seenfrom this Table, the compounds of this invention, i.e. compounds 3through 5, are effective inhibitors of SRS-A synthesis.

Certain of these compounds, e.g. test compounds 3 through 5 of Tablewere only moderately effective inhibitors of Δ¹² -lipoxygenase whereascompounds 6 through 8 were not effective either in inhibiting theactivity of other body factors such as Δ¹² -lipoxygenase andprostaglandin endoperoxide. These results show that the compounds ofthis invention are relatively selective in inhibiting SRS-A synthesiswithout substantially inhibiting other enzymes when compared to standardSRS-A synthesis inhibitors, i.e. the compounds 1 and 2.

                                      TABLE                                       __________________________________________________________________________                                   Δ.sup.12 -                                                                        PROSTAGLANDIN                                      SRS-A SYNTHESIS  LIPOXYGENASE                                                                            ENDO PEROXIDE                                      (Rat Peritoneal Cells)                                                                         (Human Platelet)                                                                        SYNTHASE                             TEST COMPOUNDS                                                                              % Inhibition at 10 μM                                                                 IC.sub.50 (μM)                                                                   IC.sub.50 (μM)                                                                       IC.sub.50 (μM)                    __________________________________________________________________________    1. 5,8,11,14-Eicosatetraynoic                                                               100 ± 0 (p < 0.001)                                                                   3-4   0.05-0.1  5                                     Acid                                                                         2. 9,12-Octadecadiynoic                                                                     87 ± 1 (p < 0.001)                                                                    3     ≧100                                                                             0.1-1.0                               Acid                                                                          Compound 3.  81 ± 6 (p < 0.01)                                                                     4-5   10-100    10-100                                Compound 4.  85 ± 8 (p < 0.001)                                                                    <10   10-100    --                                    Compound 5.  100 ± 0 (p < 0.001)                                                                   ˜1-3                                                                          13        >100                                  Compound 6.  100 ± 0 (p < 0.001)                                                                   ˜1-3                                                                          ˜100                                                                              >100                                  Compound 7.  86 ± 8 (p < 0.001)                                                                    <10   ˜100                                      Compound 8.  88 ± 6 (p < 0.001)                                                                    <10   >100                                           __________________________________________________________________________

EXAMPLE 33 Capsule Formulation of (Z,Z)-11,14-eicosadien-5,8-diynoicacid

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z,Z)-11,14-                                                                  eicosadien-                                                                   5,8-diynoic acid                                                                          0.1     0.5   5.0   10.0  25.0                               2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                    

Procedures

1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.

2. Mix with Items 4 and 5 and fill on capsule machine.

EXAMPLE 34 Tablet Formulation (Wet Granulation) of(Z,Z)-11,14-eicosadien-5,8-diynoic acid

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z,Z)-11,14-                                                                  eicosadien-                                                                   5,8-diynoic acid                                                                          0.1     0.5   5.0   10.0  25.0                               2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                Starch      10.0    10.0  10.0  20.0  30.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.

2. Mix with Item 5 and compress on a suitable press.

EXAMPLE 35 Tablet Formulation (Direct Compression) of(Z,Z)-11,14-eicosdaien-5,8-diynoic acid

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z,Z)-11,14-                                                                  eicosadien-                                                                   5,8-diynoic acid                                                                          0.1     0.5   5.0   10.0  25.0                               2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.5     1.5   1.5   2.0   2.5                                     Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.

2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.

3. Compress on a suitable press.

EXAMPLE 36 Capsule Formulations of (Z,Z)-11,14-eicosadien-5,8-diynoicacid methyl ester

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z,Z)-11,14-                                                                  eicosadien-5,8-                                                               diynoic acid                                                                  methyl ester                                                                              0.1     0.5   5.0   10.0  25.0                               2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                    

Procedures

1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.

2. Mix with Items 4 and 5 and fill on capsule machine.

EXAMPLE 37 Tablet Formulation (Direct Compression) of(Z,Z)-11,14-eicosadien-5,8-diynoic acid methyl ester

    ______________________________________                                                   mg/tablet                                                          Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        2.   (Z,Z)-11,14-                                                                  eicosadien-5,8-                                                               diynoic acid                                                                  methyl ester                                                                              0.1     0.5   5.0   10.0  25.0                               2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.5     1.5   1.5   2.0   2.5                                     Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.

2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.

3. Compress on a suitable press.

EXAMPLE 38 Tablet Formulation (Wet Granulation) of(Z,Z)-11,14-eicosadien-5,8-diynoic acid methyl ester

    ______________________________________                                                   mg/tablet                                                          Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z,Z)-11,14-                                                                  eicosadien-5,8-                                                               diynoic acid                                                                  methyl ester                                                                              0.1     0.5   5.0   10.0  25.0                               2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                Starch      10.0    10.0  10.0  20.0  30.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.

2. Mix with Item 5 and compress on a suitable press.

EXAMPLE 39 Capsule Formulation of2-(1-fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   2-(1-fluoro-                                                                  nonadec-13(Z)-                                                                en-4,7-diynyl)-                                                               4,5-dihydro-4,4-                                                              dimethyloxazole                                                                           0.1     0.5   5.0   10.0  25.0                               2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                    

Procedures

1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.

2. Mix with Items 4 and 5 and fill on capsule machine.

EXAMPLE 40 Tablet Formulation (Direct Compression) of2-(1-fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

    ______________________________________                                                   mg/tablet                                                          Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   2-(1-fluoro-                                                                  nonadec-13(Z)-                                                                en-4,7-diynyl)-                                                               4,5-dihydro-4,4-                                                              dimethyloxazole                                                                           0.1     0.5   5.0   10.0  25.0                               2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.5     1.5   1.5   2.0   2.5                                     Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.

2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.

3. Compress on a suitable press.

EXAMPLE 41 Tablet Formulation (Wet Granulation) of2-(1-fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

    ______________________________________                                                   mg/tablet                                                          Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   2-(1-fluoro-                                                                  nonadec-13(Z)-                                                                en-4,7-diynyl)-                                                               4,5-dihydro-4,4-                                                              dimethyloxazole                                                                           0.1     0.5   5.0   10.0  25.0                               2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                Starch      10.0    10.0  10.0  20.0  30.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.

2. Mix with Item 5 and compress on a suitable press.

EXAMPLE 42 Capsule Formulation of(Z)-2-(13-Nonadecene-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

    ______________________________________                                                   mg/capsule                                                         Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z)-2-(13-                                                                    nonadecen-4,7-                                                                diynyl)-                                                                      4,5-dihydro-4,4-                                                              dimethyl-                                                                     oxazole     0.1     0.5   5.0   10.0  25.0                               2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                    

Procedures

1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.

2. Mix with Items 4 and 5 and fill on capsule machine.

EXAMPLE 43 Tablet Formulation (Wet Granulation) of(Z)-2-(13-nonadecene-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole

    ______________________________________                                                   mg/tablet                                                          Item Ingredients 0.1     0.5   5.0   10.0  25.0                               ______________________________________                                        1.   (Z)-2-(13-                                                                    nonadecene-4,7-                                                               diynyl)-                                                                      4,5-dihydro-4,4-                                                              dimethyl-                                                                     oxazole     0.1     0.5   5.0   10.0  25.0                               2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                Starch      10.0    10.0  10.0  20.0  30.0                               5.   Magnesium                                                                     Stearate    1.0     1.0   1.0   2.0   3.0                                     Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                    

Procedure

1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.

2. Mix with Item 5 and compress on a suitable press.

We claim:
 1. A compound of the formula ##STR31## wherein R is ##STR32##R₁ is hydrogen or fluoro; A and B are individually hydrogen or takentogether from a carbon to carbon bond with a cis configuration; E and Gare individually hydrogen or taken together form a carbon to carbon bondwith a cis configuration with the proviso that at least one of A and Btaken together or E and D taken together form a carbon to carbon bondwith a cis configuration; and R₂ and R₃ are hydrogen or lower alkyl; orpharmaceutically acceptable salts thereof.
 2. The compound of claim 1where R₁ is hydrogen.
 3. The compound of claim 2 wherein said compoundis (Z)-2-(13-nonadecene-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole. 4.The compound of claim 2 where R₁ is fluoro.
 5. The compound of claim 4wherein said compound is2-(1-fluorononadec-13(Z)-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole.6. A compound of the formula ##STR33## wherein R is ##STR34## and R₂ andR₃ are hydrogen; and Δ designates a cis double bond.
 7. The compound ofclaim 5 wherein said compound is2-[1-fluorononadeca-7(Z),10(Z),13(Z)-trien-4-ynyl]-4,5-dihydro-4,4-dimethyloxazole.8. A compound of the formula: ##STR35## wherein R is ##STR36## R₁ ishydrogen, alkali metal, alkaline earth metal, or lower alkyl; and R₂ andR₃ are hydrogen or lower alkyl, or magnesium halide salts thereof. 9.The compound of claim 8 wherein said compound is2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole.